The present invention relates to a novel process for the preparation of Flecainide or a precursor thereof, to a novel intermediate used in this process and its preparation.
Flecainide (2,5-bis(2,2,2-trifluoroethoxy-N-(2-piperidylmethyl)benzamide is an effective antiarrythmic drug that acts on the cell membrane to reduce fast inward depolarization current.
One prior art method for preparing Flecainide [IV], disclosed in British Patent Application No. 2,045,760, starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III]. 
Compound [III] is prepared by a multi-stage process, comprising the conversion of 1,4-dibromobenzene or hydroquinone to 1,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
The one step process has a serious disadvantage in that the acid chloride reacts non-selectively with both nitrogen atoms of the 2-(aminomethyl)piperidine, resulting in a mixture of the two acylated isomers. This is the main reason why the two-step process via the pyridine intermediate is commercially preferred. A further disadvantage is due to the fact that the acid chloride intermediate disclosed in GB 2,045,760A is a liquid which cannot be stored for long periods of time, but must be used immediately after it is prepared.
Trifluoroethoxybenzoic acids of the formula [I] are useful intermediates in the pharmaceutical industry. 
These compounds can be obtained by the reaction of hydroxybenzoic acids of the general formula [V] with 2,2,2-trifluoroethyl triflate [VI] according to Scheme 1 (Banitt, E. H. et al., J. Med. Chem. 18:1130 (1975)). 
This method requires the use of trifluoroethyl triflate [VI] which is costly and not easily available commercially.
Another method (GB2045760A) involves the oxidation of the acetyl group of trifluoroethoxyacetophenones with hypochlorite as shown in Scheme 2. However, partial halogenation of the benzene ring may occur in this process, thus making it difficult for production of the (2,2,2-trifluoroethoxy)benzoic acids [I] as pharmaceutical precursors. 
There is only one reported example of copper assisted fluoroalkoxy-de-halogenation of a 2-bromo-1-naphthalenecarboxylic acid derivative (Wrobel J. et al., J. Med. Chem. 34, 2504 (1991)). This example is very specific since it describes the de-halogenation of an active halogen, i.e. bromine, which is also located in a highly activated ortho position to a carboxylic group.
It is an object of the invention to provide a novel process for the preparation of trifluoroethoxy benzoic acid derivatives, in particular Flecainide, and their pharmaceutically acceptable salts, which is free of the above-mentioned disadvantages, starting with commercially available halobenzoic acids and involving the use of simple reagents and low cost solvents, to afford high overall yield of the product.
The above object is achieved in accordance with the present invention which, in one aspect thereof, provides a process for preparing a compound of formula (A): 
wherein
Ar represents a benzene ring;
R is hydrogen or a substituent selected from alkyl, alkoxy, alkylthio, halogen, haloalkyl, haloalkoxy, haloalkylthio, phenyl, phenoxy, benzyloxy, N-substituted or N,N-disubstituted amino groups, nitro, alkoxycarbonyl, cyano, carboxyl and when m greater than 1 the R substituents may be the same or different;
Rxe2x80x2 is a 2-piperidyl or 2-pyridyl radical,
n is 1, 2 or 3;
m is 0, 1, 2, 3 or 4; where n+mxe2x89xa65; and
pharmaceutically acceptable salts thereof, which process comprises the steps of:
a) reacting a halobenzoic acid or a salt thereof of the formula [II]
wherein
Ar, R, n and m are as defined above;
M is hydrogen or a metal, ammonium or phosphonium cation; and
X is Cl, Br or I, and when n greater than 1 the X substituents may be the same or different;
with 2,2,2-trifluoroethanol in the presence of a strong base and a copper containing material, if desired followed by acidification to obtain a compound of formula [I]
wherein Ar, R, m and n are as defined above, and
b) converting the product obtained in step a) above into the compound of formula (A) or a pharmaceutically acceptable salt thereof.
According to a specific embodiment, the present invention provides a process for the preparation of a compound of formula (Axe2x80x2): 
wherein Rxe2x80x2 is a 2-piperidyl or 2-pyridyl radical, and pharmaceutically acceptable salts thereof.
Step b) above may be carried out by known procedures, such as those described in GB 2,045,760A or in Chem. Abs. 114:122069. Alternatively, according to a preferred embodiment, the present invention provides a novel process for step b). This novel process comprises:
(i) reacting a compound of formula [I] or a salt thereof, with a haloacetonitrile of the formula XCH2CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of the formula: 
(ii) reacting the cyanomethyl ester with an amine of the formula Rxe2x80x2CH2NH2 where Rxe2x80x2 is as defined above and, if desired,
(iii) converting the compound of the formula (A) into a pharmaceutically acceptable salt thereof.
Preferably, the halobenzoic acid in step a) is a compound of formula [XVII] or a salt thereof and the product of step a) is (2,2,2-trifluoroethoxy)-benzoic acid [III] or a salt thereof 
wherein:
X3 is Br or I, X4 is Cl, Br or I, or one of X3 and X4 may also be CF3CH2Oxe2x80x94. (2,2,2-Trifluoroethoxy)benzoic acid [III] or a salt thereof may be converted in step b) into a compound of the formula (Axe2x80x2) either by known methods or by the novel process of the present invention, which particularly comprises of:
(i) reacting 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III] or a salt thereof, with a haloacetonitrile of the formula XCH2CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid of the formula 
ii) reacting the cyanomethyl ester with an amine of the formula Rxe2x80x2CH2NH2 where Rxe2x80x2 is as defined above and, if desired,
iii) converting the resulting product of the formula (Axe2x80x2) 
xe2x80x83into a pharmaceutically acceptable salt thereof. Axe2x80x2 represents Flecainide when Rxe2x80x2 is 2-piperidyl.
In accordance with another aspect of this invention, there is provided the novel cyanomethyl ester of 2,5-bis(2,2,2-trifuoroethoxy)benzoic acid having the formula above. The novel intermediate of the present invention is a stable, solid compound, obtainable in high yield, which can be easily purified by crystallization and stored for long periods of time.
(2,2,2-Trifluoroethoxy)benzoic acids [I] or salts thereof obtained in step a) of the process of the present invention may contain one or more 2,2,2-trifluoroethoxy groups. Additionally, other substituents R as defined above may be present on the aromatic ring.
As defined herein, the term xe2x80x9chalobenzoic acidxe2x80x9d includes benzoic acids containing one or more halogen atoms and optionally additional substituents as defined for R above.
According to a preferred embodiment of the present invention, a chloro-, bromo- or iodo-benzoic acid is reacted with a metal trifluoroethoxide in the presence of copper iodide or bromide in an aprotic solvent. Such aprotic solvent may be a dipolar aprotic solvent or an N-containing heterocycle or mixtures thereof. Examples of dipolar aprotic solvents are N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, DMSO and hexamethylphosphoramide. N-containing heterocyclic solvents used in the present invention are pyridine, picolines, lutidines, collidines, methylethylpyridine (MEP), other substituted pyridines, quinoline and substituted quinolines.
The reaction is preferably carried out at a temperature in the range of from ambient temperature to 170xc2x0 C.
In the process of the invention, preferably at least one mole of 2,2,2-trifluoroethanol is used per each halogen atom of the halobenzoic acid [II] which is desired to be replaced by a trifluoroethoxy group. However, a large molar excess of 2,2,2-trifluoroethanol can be used in which cases this reactant may also serve as a solvent. At least one mole of 2,2,2-trifluoroethanol per mole of the strong base should be used and the mole ratio of the copper containing compound to the halobenzoic acid [I] can be in the range of 0.01 to 2:1.
Suitable copper containing materials are for example: copper salts, copper oxides, metallic copper, copper alloys, etc.
Compounds of formula [I] are converted in step b) into a desired compound of formula (A) either by known procedures or by a novel process which constitutes a further aspect of the present invention.
According to one prior art method described in GB 2,045,760A, 1,4-bis(2,2,2-trifluoroethoxy)benzene is acetylated to form the corresponding acetophenone, which is then oxidized to the benzoic acid derivative. The benzoic acid derivative is converted into the acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one stepxcx9cor with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
According to another prior art method described in Chem. Abs. 114:122069, 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid may be converted into the corresponding acid chloride, which is reacted with 2-azaindolizidine to give the heterocyclic amide [XX] as the HCl salt, which is selectively hydrogenated to Flecainide, followed by salification with glacial acetic acid. 
Alternatively, as mentioned above, step b) is carried out by a novel process which comprises:
(i) reacting a compound of formula [I] or a salt thereof, with a haloacetonitrile of the formula XCH2CN, where X is Cl, Br or I, if necessary in the presence of an inorganic or organic base, to form the cyanomethyl ester of the formula: 
(ii) reacting the cyanomethyl ester with an amine of the formula Rxe2x80x2CH2NH2 where Rxe2x80x2 is as defined above and, if desired,
(iii) converting the compound of the formula (A) into a pharmaceutically acceptable salt thereof.
Preferably, (2,2,2-trifluoroethoxy)benzoic acid [III] or a salt thereof is obtained in step a) of the process of the invention from a halobenzoic acid of the formula [XVII] and is subsequently reacted with a haloacetonitrile of the formula XCH2CN wherein X is Cl, Br or I, preferably Cl, in the presence of an inorganic or organic base, to give at the end of the process a compound of formula (Axe2x80x2). 
In the above formulae, X3 is Br or I, X4 is Cl, Br or I, or one of X3 and X4 may also be CF3CH2Oxe2x80x94; Rxe2x80x2 is a 2-piperidyl or 2-pyridyl radical. When Rxe2x80x2 is 2-piperidyl, then the product is Flecainide or a salt thereof.
It was shown by Schwyzer et al. (Helvetica Chimica Acta, 1955, v. 38,69; 80;83) that cyanomethyl esters of aliphatic amino acids react selectively with primary amino groups. R. Buyle in Helvetica Chimica Acta, 1964, v. 47, p. 2444, showed that benzylamine reacts with cyanomethyl benzoate considerably slower than with cyanomethyl acetate. The present invention is based on the unexpected finding that 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid activated by conversion to its cyanomethyl ester may react selectively and with high yield with primary amino groups of amines of the formula RCH2NH2 
Thus, in step b) of the process, the cyanomethyl ester is reacted with an amine of the formula RCH2NH2 where R is as defined above, optionally in a suitable, inert solvent. Preferably, the reaction may be carried out by mixing together 2-(aminomethyl)piperidine with the cyanomethyl ester in a solvent such as 1,2-dimethoxyethane or ethyl acetate, to yield Flecainide (I) in a high yield.
The optional conversion of Flecainide into a pharmaceutically acceptable salt such as the acetate salt, is carried out by conventional methods.
The present invention will be described in more detail with the aid of the following non-limiting examples.